Structure-based design of a thiazolidinedione which targets the mitochondrial protein mitoNEET.

Several PPAR-gamma agonists containing a thiazolidinedione moiety (referred to as glitazones) have been proposed to be neuroprotective and appear to alter mitochondrial function. Recently, a search for mitochondrial proteins that bind pioglitazone identified a novel protein, mitoNEET, which was later shown to regulate the oxidative capacity of the mitochondria. This identified an alternative target for the glitazones suggesting a possible new drug target for the treatment of neurodegenerative diseases.

Glucose stimulates cholesterol 7alpha-hydroxylase gene transcription in human hepatocytes.

Bile acids play important roles in the regulation of lipid, glucose, and energy homeostasis. Recent studies suggest that glucose regulates gene transcription in the liver. The aim of this study was to investigate the potential role of glucose in regulation of bile acid synthesis in human hepatocytes.

Resveratrol in the chemoprevention and treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers and lethal diseases in the world. Although the majority of HCC cases occur in developing countries of Asia and Africa, the prevalence of liver cancer has risen considerably in Japan, Western Europe as well as the United States. HCC most commonly develops in patients with chronic liver disease, the etiology of which includes viral hepatitis (B and C), alcohol, obesity, iron overload and dietary carcinogens, including aflatoxins and nitrosamines.

Histochemical analyses of tissue-engineered human menisci.

The field of tissue engineering remains one of the least explored areas of current meniscal research but holds great promise. In this investigation, meniscal fibrochondrocytes were isolated from fresh human meniscal tissue and seeded onto synthetic polyglycolic acid (PGA) scaffolds. Constructs were implanted into the dorsal subcutaneous space of athymic nude mice.

Chemopreventive doses of resveratrol do not produce cardiotoxicity in a rodent model of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), one of the most lethal cancers, results in more than one million fatalities worldwide every year. In view of the limited therapeutic alternatives and poor prognosis of liver cancer, preventive control approaches, notably chemoprevention, have been considered to be the best strategy in lowering the present prevalence of the disease. Resveratrol, a naturally occurring antioxidant and antiinflammatory agent found in grapes and red wine, inhibits carcinogenesis with a pleiotropic mode of action.

Regulation of glutamatergic and GABAergic neurotransmission in the chick nucleus laminaris: role of N-type calcium channels.

Neurons in the chicken nucleus laminaris (NL), the third order auditory nucleus involved in azimuth sound localization, receive bilaterally segregated (ipsilateral vs contralateral) glutamatergic excitation from the cochlear nucleus magnocellularis and GABAergic inhibition from the ipsilateral superior olivary nucleus (SON). Here, I investigate the voltage-gated calcium channels (VGCCs) that trigger the excitatory and the inhibitory transmission in the NL. Whole-cell recordings were performed in acute brainstem slices.

Beta-adrenoceptor stimulation of alveolar fluid clearance is increased in rats with heart failure.

The alveolar epithelium plays a critical role in resolving pulmonary edema. We thus hypothesized that its function might be upregulated in rats with heart failure, a condition that severely challenges the lung's ability to maintain fluid balance. Heart failure was induced by left coronary artery ligation.

The serotonin 5-HT6 receptor: a viable drug target for treating cognitive deficits in Alzheimer's disease.

The serotonin 6 receptor is attracting attention as an etiological contributor in cognition deficits in diseases such as Alzheimer's disease, anxiety/depression and schizophrenia. In this review, we discuss the role of this recently discovered G protein-coupled receptor in cognition and memory, particularly in Alzheimer's disease. A surge in publications that describe the development of ligands for this receptor have recently come to light, underscoring the emerging interest in this receptor as a drug target.

Assessing the impact on patient-physician interaction when physicians use personal digital assistants: a Northeastern Ohio Network (NEON) study.

Background: The effects of the use of technological devices on dimensions that affect the physician-patient relationship need to be well understood.

Objectives: Determine patients' perceptions of physicians' personal digital assistant (PDA) use, comparing the results across 8 physician-patient dimensions important to clinical interactions.

Results: Patients completed anonymous surveys about their perceptions of physician PDA use.

Advanced osteoarthritis in humans is associated with altered collagen VI expression and upregulation of ER-stress markers Grp78 and bag-1.

To test the hypothesis that a perturbation of endoplasmic reticulum (ER) function is involved in the pathogenesis of osteoarthritis (OA), articular cartilage was isolated from non-OA patients secondary to resection of osteo- or chondrosarcomas. Intra-joint samples of minimal and advanced osteoarthritic cartilage were isolated from patients undergoing total knee arthroplasty and scored for disease severity. Glucose-regulated protein-78 (grp78) and bcl-2-associated athanogene-1 (bag-1) were detected via immunofluorescence as markers of non-homeostatic ER function.

Development of bone and cartilage in tissue-engineered human middle phalanx models.

Human middle phalanges were tissue-engineered with midshaft scaffolds of poly(L-lactide-epsilon-caprolactone) [P(LA-CL)], hydroxyapatite-P(LA-CL), or beta-tricalcium phosphate-P(LA-CL) and end plate scaffolds of bovine chondrocyte-seeded polyglycolic acid. Midshafts were either wrapped with bovine periosteum or left uncovered. Constructs implanted in nude mice for up to 20 weeks were examined for cartilage and bone development as well as gene expression and protein secretion, which are important in extracellular matrix (ECM) formation and mineralization.

d -Limonene sensitizes docetaxel-induced cytotoxicity in human prostate cancer cells: Generation of reactive oxygen species and induction of apoptosis.

Background: Clinical trials have shown that docetaxel combined with other novel agents can improve the survival of androgen-independent prostate cancer patients. d -Limonene, a non-nutrient dietary component, has been found to inhibit various cancer cell growths without toxicity. We sought to characterize whether a non-toxic dose of d -limonene may enhance tumor response to docetaxel in an in vitro model of metastatic prostate cancer.

Forkhead box transcription factor O1 inhibits cholesterol 7alpha-hydroxylase in human hepatocytes and in high fat diet-fed mice.

The conversion of cholesterol to bile acids is the major pathway for cholesterol catabolism. Bile acids are metabolic regulators of triglycerides and glucose metabolism in the liver. This study investigated the roles of FoxO1 in the regulation of cholesterol 7alpha-hydroxylase (CYP7A1) gene expression in primary human hepatocytes.

Cancer prevention and treatment with resveratrol: from rodent studies to clinical trials.

Resveratrol (3,4',5-trihydroxy-trans-stilbene) is a dietary polyphenol derived from grapes, berries, peanuts, and other plant sources. During the last decade, resveratrol has been shown to possess a fascinating spectrum of pharmacologic properties. Multiple biochemical and molecular actions seem to contribute to resveratrol effects against precancerous or cancer cells.

Gender differences in the association between antidepressant use and restless legs syndrome.

Contradictory results have been reported for the association between antidepressant use and Restless Legs Syndrome (RLS). Our aim was to clarify the relationship and examine possible gender differences. We interviewed 1,693 veterans receiving primary care from the Cleveland VA Medical Center and obtained prescription drug information from their medical records.

The Ventriloscope: 'am I hearing things?'.

Background: Knowledge of the benefits of incorporating medical simulation into healthcare curricula is rapidly increasing. Though impeded by the high cost of complicated technology, medical simulation devices offer the ability to provide safe and controlled training environments, exposure to rare clinical scenarios, as well as unlimited training opportunities.

Methods: This report describes a novel, inexpensive method of broadcasting normal and abnormal auscultatory findings to a relatively normal appearing stethoscope for use in training of healthcare professionals.

Sources of cholinergic input to the inferior colliculus.

We combined retrograde tracing with immunohistochemistry for choline acetyltransferase to identify the source of cholinergic input to the inferior colliculus (IC) in guinea pigs. Injection of a retrograde tracer into one IC labeled cells in many brainstem nuclei. Retrogradely-labeled cells that were also immunoreactive for choline acetyltransferase were identified in two nuclei in the midbrain tegmentum: the pedunculopontine tegmental nucleus (PPT) and the laterodorsal tegmental nucleus (LDT).

HSV-2 ICP34.5 protein modulates herpes simplex virus glycoprotein processing.

The ICP34.5 gene from HSV-2 strain 333 was cloned and, when expressed in Vero cells, enhanced the efficiency and extent of glycoprotein processing of glycoprotein C (gC1), a representative viral glycoprotein, during infection with HSV-1 SP7. The ICP34.

Hepatocyte nuclear factor 4alpha regulation of bile acid and drug metabolism.

The hepatocyte nuclear factor 4alpha (HNF4alpha) is a liver-enriched nuclear receptor that plays a critical role in early morphogenesis, fetal liver development, liver differentiation and metabolism. Human HNF4alpha gene mutations cause maturity on-set diabetes of the young type 1, an autosomal dominant non-insulin-dependent diabetes mellitus. HNF4alpha is an orphan nuclear receptor because of which the endogenous ligand has not been firmly identified.

Incidental findings in the cervical spine at CT for trauma evaluation.

Objective: CT is the standard of care for assessment of traumatic injuries. Because of the detail depicted with this technique, findings incidental to the injury are easily detected. We sought to determine the frequency and types of incidental findings in the cervical spines of trauma patients undergoing CT.

Gene expression in slipped capital femoral epiphysis. Evaluation with laser capture microdissection and quantitative reverse transcription-polymerase chain reaction.

Background: Slipped capital femoral epiphysis is a poorly understood condition affecting adolescents. Prior studies have suggested that the etiology may be related to abnormal collagen in the growth plate cartilage, but we are not aware of any investigations analyzing collagen or other structural proteins on a molecular level in the affected tissue. This study was performed to evaluate expression of mRNA for key structural molecules in growth plate chondrocytes of patients with slipped capital femoral epiphysis.

IL-1beta-induced cortisol stimulates lung fluid absorption in fetal guinea pigs via SGK-mediated Nedd4-2 inhibition.

We tested the hypothesis that interleukin (IL)-1beta-induced cortisol synthesis stimulates distal lung fluid absorption in fetal guinea pigs via induction of serum- and glucocorticoid-regulated kinase (SGK) and inhibition of neural precursor cell expressed, developmentally downregulated protein 4-2 (Nedd4-2). IL-1beta was subcutaneously administered daily to timed-pregnant guinea pigs over 3 days. Fetuses were obtained by abdominal hysterotomy at gestation day (GD)61 and GD68 and instilled with an isosmolar 5% albumin solution into the lungs.

Polycyclic compounds: ideal drug scaffolds for the design of multiple mechanism drugs?

Recently there has been a resurging interest in developing multi-functional drugs to treat diseases with complex pathological mechanisms. Such drug molecules simultaneously target multiple etiologies that have been found to be important modulators in specific diseases. This approach has significant promise and may be more effective than using one compound specific for one drug target or, by a polypharmaceutical approach, using a cocktail of two or more drugs.